Functional selectivity challenges the traditional concept of intrinsic efficacy in pharmacology, where ligands are classified based on their ability to activate or inhibit receptor responses. Recent data show that many ligands can differentially activate signaling pathways through a single G protein-coupled receptor (GPCR), suggesting that functional selectivity, agonist-directed trafficking, and biased agonism are key phenomena. These mechanisms involve differences in ligand-induced conformational states, G protein diversity, scaffolding, and receptor oligomers. Functional selectivity has significant implications for drug discovery, as it allows for the design of ligands that selectively activate specific receptor functions, optimizing therapeutic outcomes. The concept of intrinsic efficacy, once considered system-independent, is now questioned, as data from serotonin, opioid, dopamine, vasopressin, and adrenergic receptors demonstrate that receptor responses vary depending on the ligand and signaling pathway. This has led to the need for revised pharmacological conventions to incorporate these new insights. Functional selectivity is evident in the 5-HT2 receptor system, where ligands like bufotenin and TFMPP exhibit different agonist activities for AA release and IP accumulation. Similarly, in the 5-HT2A receptor, compounds like LSD and DOB show differential signaling through PLC-IP and AA pathways. These findings challenge the classical view that intrinsic efficacy is a constant property of a ligand-receptor complex. The 5-HT2A receptor also mediates the release of arachidonic acid (AA) and the formation of endocannabinoids, highlighting the complexity of receptor signaling. Functional selectivity is not limited to serotonin receptors; it has been observed in opioid, adrenergic, and vasopressin receptors. For example, the μ-opioid receptor exhibits differential endocytosis and signaling based on ligand identity, while the β2-adrenergic receptor shows distinct conformational changes and signaling outcomes depending on the ligand. The V2 vasopressin receptor also demonstrates functional selectivity, with mutations affecting receptor signaling and internalization. The concept of functional selectivity has implications for drug development, as seen in the case of aripiprazole, an atypical antipsychotic that acts as a partial agonist at the D2 receptor and antagonist at the 5-HT2A receptor. This dual action contributes to its therapeutic effects by stabilizing dopamine pathways. Functional selectivity is also relevant in the context of receptor oligomerization, where different ligands can induce distinct conformational changes and interactions, leading to varied signaling outcomes. The study of these mechanisms is crucial for understanding GPCR signaling and developing more effective therapeutics. The integration of computational and experimental approaches is essential for elucidating the structural and functional basis of functional selectivity, which has the potential to revolutionize pharmacological research and drug discovery.Functional selectivity challenges the traditional concept of intrinsic efficacy in pharmacology, where ligands are classified based on their ability to activate or inhibit receptor responses. Recent data show that many ligands can differentially activate signaling pathways through a single G protein-coupled receptor (GPCR), suggesting that functional selectivity, agonist-directed trafficking, and biased agonism are key phenomena. These mechanisms involve differences in ligand-induced conformational states, G protein diversity, scaffolding, and receptor oligomers. Functional selectivity has significant implications for drug discovery, as it allows for the design of ligands that selectively activate specific receptor functions, optimizing therapeutic outcomes. The concept of intrinsic efficacy, once considered system-independent, is now questioned, as data from serotonin, opioid, dopamine, vasopressin, and adrenergic receptors demonstrate that receptor responses vary depending on the ligand and signaling pathway. This has led to the need for revised pharmacological conventions to incorporate these new insights. Functional selectivity is evident in the 5-HT2 receptor system, where ligands like bufotenin and TFMPP exhibit different agonist activities for AA release and IP accumulation. Similarly, in the 5-HT2A receptor, compounds like LSD and DOB show differential signaling through PLC-IP and AA pathways. These findings challenge the classical view that intrinsic efficacy is a constant property of a ligand-receptor complex. The 5-HT2A receptor also mediates the release of arachidonic acid (AA) and the formation of endocannabinoids, highlighting the complexity of receptor signaling. Functional selectivity is not limited to serotonin receptors; it has been observed in opioid, adrenergic, and vasopressin receptors. For example, the μ-opioid receptor exhibits differential endocytosis and signaling based on ligand identity, while the β2-adrenergic receptor shows distinct conformational changes and signaling outcomes depending on the ligand. The V2 vasopressin receptor also demonstrates functional selectivity, with mutations affecting receptor signaling and internalization. The concept of functional selectivity has implications for drug development, as seen in the case of aripiprazole, an atypical antipsychotic that acts as a partial agonist at the D2 receptor and antagonist at the 5-HT2A receptor. This dual action contributes to its therapeutic effects by stabilizing dopamine pathways. Functional selectivity is also relevant in the context of receptor oligomerization, where different ligands can induce distinct conformational changes and interactions, leading to varied signaling outcomes. The study of these mechanisms is crucial for understanding GPCR signaling and developing more effective therapeutics. The integration of computational and experimental approaches is essential for elucidating the structural and functional basis of functional selectivity, which has the potential to revolutionize pharmacological research and drug discovery.